Enantioselective Conjugate Addition Reactions via Enamine Activation

Enantioselective Conjugate Addition Reactions via Enamine Activation 

By Jose L. Vieario, Dolores Badia, Luisa Carrillo and Efraim Reyes 

1 Factors Influencing the Stereocontrol in Michael Additions Proceeding via Enamine Activation 

In this context, controlling the geometry of the formed enamine intermediate shows up as the first very important issue that has to be controlled if a highly stereoselective reaction is desired. Condensation of a secondary amine with an aldehyde or a ketone can lead to the formation of two diastereoisomers, Z or E, in varying proportions depending on the nature of the carbonyl reagent and the 

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Enantioselective Conjugate Addition Reactions via. Enamine Activation... 

First, the catalyst forms the enamine with the lineal aldehyde that attacks the nitrostyrene via a Michael addition. The catalyst was hydrolyzed and forms the iminium ion with the enal. This activated form of the enal reacts with the previously formed nitroalkane via a Michael addition. During this second conjugate addition, a new enamine intermediate is formed that cyclize via a intramolecular aldol reaction to afford cyclohecenes after dehydration of the aldol product. The final cyclohexenes were obtained in good yields, moderate diastereoselectivities, and almost complete enantioselectivity. 

The majority of the Michael-type conjugate additions are promoted by amine-based catalysts and proceed via an enamine or iminium intermediate species. Subsequently, Jprgensen et al. [43] explored the aza-Michael addition of hydra-zones to cyclic enones catalyzed by Cinchona alkaloids. Although the reaction proceeds under pyrrolidine catalysis via iminium activation of the enone, and also with NEtj via hydrazone activation, both methods do not confer enantioselectivity to the reaction. Under a Cinchona alkaloid screen, quinine 3 was identified as an effective aza-Michael catalyst to give 92% yield and 1 3.5 er (Scheme 4). 

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